m6A-RNA demethylase ALKBH5 inhibitors for the treatment of glioblastoma

m6A-RNA 去甲基化酶 ALKBH5 抑制剂用于治疗胶质母细胞瘤

基本信息

批准号：
10043670
负责人：
TARIQ M RANA
金额：
$ 43.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10043670
关键词：
3-Dimensional Adult Alkylation Biological Assay Biological Models Brain Neoplasms Cells Characteristics Chemicals Chemotherapy and/or radiation Child Collaborations Deposition Drug Design Drug Kinetics Enzyme Kinetics Enzymes Gene Expression Glioblastoma Goals Homologous Gene Homologous Protein In Vitro Infiltration Life Expectancy Longevity Malignant Neoplasms Messenger RNA Modeling Modification Mus Nucleotides Organoids Outcome Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Play Population Post-Transcriptional Regulation Property RNA RNA metabolism Radiation therapy Reader Recombinants Recurrence Regulation Resistance Role Site Survival Rate Testing Therapeutic Agents Undifferentiated Work antiproliferative agents chemical property chemotherapeutic agent design drug development drug discovery epitranscriptomics improved in vivo in vivo Model inhibitor/antagonist innovation knock-down novel outcome forecast repaired small molecule inhibitor stem therapeutic target tumor tumor progression tumorigenesis

项目摘要

Epitranscriptomics is an emerging field that seeks to identify and understand chemical modifications in RNA; the enzymes that deposit, remove, and interpret the modifications (writers, erasers, and readers, respectively); and their effects on gene expression via regulation of RNA metabolism, function, and localization. Glioblastoma multiforme (GBM) is the deadliest brain tumor identified in both adults and children, with an average life expectancy of 15 months. GBM is characterized by high rates of both tumor infiltration and recurrence and is often resistant to treatment with radiation and chemotherapy. These characteristics have been attributed to the presence of undifferentiated glioblastoma tumor-initiating cells or glioblastoma stem-like tumor initiating cells (GSCs). Recent studies have shown that cells depleted in N6- methyladenosine (m6A) RNA modifications are resistant to differentiation, and it is suspected that misregulation of the reversible m6A pathway may play a role in generating tumor-initiating cells and promoting tumorigenesis. ALKBH5 expression is elevated in primary and established GBM cells enriched with GSCs, and high expression is correlated with poor prognosis in GBM patients. The objective of this proposal is to identify and develop novel inhibitors of the RNA demethylase alkylation repair homolog protein 5 (ALKBH5) as potential chemotherapeutics for glioblastoma multiforme. Our project has three aims. Aim 1: to optimize leads as potent and selective inhibitors of ALKBH5 with rational drug design. Aim 2: to establish the enzymatic and cellular mechanism of action of ALKBH5 inhibitors. Aim 3: to establish ALKBH5 inhibitors as effective antiproliferative agents in GSCs. The expected outcome of this work is a chemically diverse set of the first ALKBH5 inhibitors. This project will provide a clear positive impact by providing important groundwork for developing ALKBH5-targeted treatments of GBM.

表观转录组学是一个新兴领域，旨在识别和理解化学物质 RNA 的修饰；沉积、去除和解释修饰的酶（分别为写入器、擦除器和读取器）；及其通过调控对基因表达的影响 RNA 代谢、功能和定位的研究。多形性胶质母细胞瘤（GBM）是最致命的成人和儿童均发现脑肿瘤，平均寿命为 15 个月。 GBM 的特点是肿瘤浸润率和复发率高，并且经常被对放射和化疗治疗有抵抗力。这些特征已被归因于未分化的胶质母细胞瘤肿瘤起始细胞或胶质母细胞瘤的存在干细胞样肿瘤起始细胞（GSC）。最近的研究表明，N6- 耗尽的细胞甲基腺苷（m6A）RNA修饰对分化具有抗性，怀疑可逆性 m6A 通路的错误调节可能在产生肿瘤引发中发挥作用细胞并促进肿瘤发生。 ALKBH5 表达在原代细胞中升高并已建立 GBM细胞富含GSC，高表达与GBM不良预后相关患者。该提案的目的是鉴定和开发新型 RNA 抑制剂去甲基化酶烷基化修复同源蛋白 5 (ALKBH5) 作为潜在的化疗药物多形性胶质母细胞瘤。我们的项目有三个目标。目标 1：优化潜在客户，使其成为有效且有效的潜在客户具有合理药物设计的 ALKBH5 选择性抑制剂。目标 2：建立酶促和 ALKBH5 抑制剂的细胞作用机制。目标 3：建立 ALKBH5 抑制剂 GSC 中有效的抗增殖剂。这项工作的预期结果是化学多种首个 ALKBH5 抑制剂。该项目将产生明显的积极影响为开发 GBM 的 ALKBH5 靶向治疗方法提供重要基础。